One facet of the mammalian aging process is a steady decline in the regenerative potential of many tissues. Accumulation of DNA damage in the stem cells that maintain these tissues is thought to be one factor driving this gradual loss of renewal. While the cellular responses to diverse DNA lesions are increasingly well-characterized, the overall reaction of a complex organ to genotoxic stress and the processes that direct efficient tissue regeneration are still under investigation. Our efforts are focused on evaluating the acute impact of DNA damage on regenerative tissues and determining the requirements for a productive recovery from injury. ATR is a protein kinase with indispensable roles in the preservation of genomic integrity during DNA replication. Mosaic/imperfect inactivation of this kinase through inducible in vivo recombination presents a unique tool to induce DNA damage in a subset of cells populating a tissue. We are using this system to study the dynamics of the response to acute, replication-associated damage in several regenerative tissues and directly assess the genetic determinants of efficient renewal following this type of insult. We have found preliminary evidence suggesting that p53,a protein with integral roles in the cellular response to DNA damage, is required for the immediate recovery of many tissues after ATR deletion. We will extend our initial studies and determine if p53 directly facilitates the short-term repopulation of these tissues following mosaic ATR deletion. We will also evaluate the in vitro cellular consequences of ATR deletion in the context of p53 deficiency and investigate the mechanistic basis for these observations. These studies will define the importance of p53 in tissue renewal following DNA damage, provide insight into the basic molecular events that mediate the regenerative response of a tissue following injury, and further our understanding of the biological principles that govern normal physiological aging and age-associated pathological conditions. Relevance The blood, skin, and many other parts of the human body require continuous renewal throughout life for their function. Normal aging and many diseases are thought to be a result of imperfect regeneration in these and other systems. We are studying the basic biological processes that guide the renewal of several organs to better understand how defects may arise over time and contribute to aging and age-associated diseases.